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The present invention relates to a plant extract from a
low-tetrahydrocannabinol (THC) variety of Cannabis sativa subsp. sativa
for the treatment of disease. The invention further relates to the
production of the extract and pharmaceutical compositions comprising said
extract and the uses thereof.

18. A method for the treatment of therapy failures and/or refusers of a
therapy using cortisone preparations and/or calcineurin inhibitors and of
side effects of cortisone preparations and/or calcineurin inhibitors or
for the replacement therapy for the treatment using cortisone
preparations and/or calcineurin inhibitors, or the prevention or
treatment of phototoxic reactions, said method comprising: (a) obtaining
a therapeutically effective amount of plant extract from at least one of
mechanically pulverized flowers, flower-proximal leaves, stalks, roots,
and seeds of a low-tetrahydrocannabinol (THC) variety of Cannabis sativa
subspecies sativa, wherein the THC content of said extract is less than
0.5 wt.-%, or a pharmaceutical composition containing said plant extract,
and preparing a topical composition in the form of a salve, cream, gel
lotion, paste or an emulsion, and (b) administering said extract or
pharmaceutical to a patient experiencing at least one of said
dermatological conditions.

[0001] The present invention relates to a plant extract from a
low-tetrahydrocannabinol (THC) variety of Cannabis sativa subspecies
sativa for the treatment of disease. Furthermore, the invention relates
to the production of the extract and pharmaceutical or topical
compositions, which contain this extract, and the uses thereof.

[0002] The plant species cannabis belongs to the family of the hemp plants
and according to more recent findings comprises a single species
(Cannabis sativa), which occurs in 3 subspecies: industrial hemp
(Cannabis sativa subspecies sativa) L., Indian hemp (Cannabis sativa
subspecies indica) Lam., and ruderal hemp (Cannabis sativa variety
spontanea). Depending on the intended use, a differentiation is made
between intoxicant or medicinal hemp, having the drug THC, and industrial
and decorative hemp.

[0003] Cannabis is popular as a renewable raw material because of its
ready cultivation and complete usability. No herbicides are required,
because the plants already shadow the soil completely after a few days,
so that weeds no longer have light. In addition, cannabis is
extraordinarily pest-resistant and low-maintenance. Cannabis produces
more biomass than any other native useful plant, is usable in a great
manifold of ways in the economy, and is prized because of its high
durability, environmental compatibility, and low energy balance.

[0004] Manifold different products from all fields of daily life may be
produced from cannabis, such as materials (construction slabs, insulation
materials, sealants, etc.), cosmetics (creams, massage oil, soap, etc.),
foods (animal feed, oil, margarine, fats, etc.), oils, oil products (oil
for the production of printing inks and/or oil paints and putty and
spackling compounds, plastics made of oil, surfactants), papers, nonwoven
materials, pulps, natural insulation materials and fabrics (short and
long fiber).

[0005] The so-called cannabinoids are found as components in cannabis
plants. It is estimated that the resin of the cannabis plant contains
over 70 different cannabinoids, some of which, such as THC, have
psychotropic effects. The target structures of the cannabinoids upon
consumption in the human organism are the cannabinoid receptors CB-1 and
CB-2 of the endocannabinoid system. The physiological ligand of these
receptors is the arachidonic acid derivative anandamide. Currently, the
cannabinoid THC is known as a medical drug above all. Thus, for example,
semisynthetic THC, dronabinol, is usable in Germany and other countries
as a prescription narcotic (trade name Marinol.RTM.) for anorexia and
cachexia in HIV and AIDS patients, and as an antiemetic for nausea and
vomiting under cytostatic or radiation therapy in the context of a cancer
therapy. The completely synthetic THC derivative nabilon has a similar
indication. In addition, THC is in the clinical testing phase for the
treatment of glaucoma and autoimmune diseases, such as multiple
sclerosis, Crohn's disease, or ulcerative colitis. A further known, but
non-psychoactive cannabinoid from female hemp plants of Cannabis sativa
is cannabidiol (CBD). Medicinally, it relieves cramps and anxiety, is
anti-inflammatory, is an antinauseant, and reduces internal eye pressure.

[0006] WO 2005/072719 describes a plant extract, which contains at least
one acid cannabinoid and also has a low THC content of 0-5 wt.-%. This
plant extract is preferably obtained from the flowers of the varieties
Cannabis sativa subspecies sativa and Cannabis sativa subspecies indica
using liquid extraction methods, preferably under non-decarboxylating
conditions. The non-decarboxylating conditions are necessary to keep the
THC content as low as possible. In addition, the use of the plant
extracts for the production of a medication for the treatment of
inflammatory skin diseases, such as dermatitis or psoriasis, is noted,
but without any experimental data which could confirm the effectiveness.

[0007] In addition, a pharmaceutical composition is disclosed in US
2007/0060639, which comprises at least one tricyclic cannabinoid for
intranasal administration. Furthermore, the use of this pharmaceutical
composition in the event of allergic rhinitis is described.

[0008] An example of a method for producing a cannabis extract is
disclosed in US 2003/0017216 A1. For this purpose, the plant material is
admixed with a solvent, such as isopropanol, for a specific period of
time. The period of time is less than that which would be necessary to
obtain an equilibrium concentration of dissolved cannabinoids in the
solvent. The solvent and the dissolved cannabinoids are subsequently
separated from the plant material.

[0009] The medicinal effectiveness of a plant extract from the low-THC
variety Cannabis sativa subspecies sativa has been completely neglected
and unstudied up to this point. A plant extract of this type not only has
the advantage of cost-effective production; through the legal cultivation
of low-THC varieties, such as Futura 75, a possible conflict in regard to
the narcotic code is also entirely avoided above all.

[0010] Diseases of the allergically and immunologically related spectrum
disorder are currently predominantly treated using cortisone preparations
(also known as glucocorticoid preparations), or calcineurin inhibitors
(from the class of cytostatics), which are subject to side effects.
However, the topically treatable extent of the skin surface is limited
both with the cortisone preparations and also with the calcineurin
inhibitors in that upon large-area application, systemically-relevant
resorption over the treated skin area must be expected. The side effects
of both therapy principles thus come to bear in a clinically relevant
manner in the entire body.

[0011] In addition to the restriction of the extent of the treatable skin
area, the therapy duration is also limited. However, many disease
symptoms which require cortisone or are only treatable by calcineurin
inhibitors, such as neurodermitis, are chronic diseases, which thus
require continuous treatment, having a significant level of suffering of
the affected patients. The treatment using calcineurin inhibitors is
limited to at most four weeks per cycle. This is similarly true for the
treatment using cortisone preparations. In both cases, after the
cessation of the therapy, which is medically required to avoid grave and
sometimes irreversible side effects, an acute exacerbation of his
symptoms ("rebound effect") which is extremely stressful for the patient,
must be expected by the patient.

[0012] There is no rigid scheme for the treatment using cortisone in
regard to the local side effects. A significant atrophy of the treated
skin area must nonetheless fundamentally be expected. In addition to
cosmetic skin changes ("leather skin"), which restrict the quality of
life, and which have significant relevance above all upon disease
affliction in the facial area, functionally relevant skin changes have
also been observed. The skin atrophy is accompanied above all with a
vulnerability of the paper-thin skin areas, which is increased upon
illness.

[0013] Although both the cortisone preparations and also the calcineurin
inhibitors display good effectiveness in the great majority of patients,
the compliance is relatively low because of the above-mentioned and thus
feared side effects. The patients frequently accept the symptoms of the
illness because of fear of the side effects of the listed substance
groups.

[0014] It is thus the object of the present invention to provide an
effective medication, which is free of side effects, for the treatment of
diseases, preferably for the treatment of diseases of the allergically
and immunologically related spectrum disorder, based on plants, which is
not only cost-effective and simple to produce, but rather also achieves
very high compliance with the patients because of its rapid and
convincing initial effect and lack of side effects (up to this point).
The object of the present invention is achieved in a first aspect by a
plant extract made of the flowers and flower-proximal leaves and/or stems
and/or roots and/or seeds, preferably the flowers and flower-proximal
leaves of a low-tetrahydrocannabinol (THC) variety of Cannabis sativa
subspecies sativa for the treatment of diseases ("plant extract"
hereafter).

[0015] In the scope of this invention, a "low-tetrahydrocannabinol (THC)
variety" is understood as a variety which, in such a plant extract, has
less than 5%, preferably less than 2%, in particular less than 0.5 to
0.2% or down to 0.1 or 0% (wt.-%) THC content. In particular, these
quantities of THC are to be understood as not representing a clinically
relevant concentration.

[0016] Surprisingly, it has been shown by the experiments performed in the
scope of the invention that this plant extract has an effectiveness
comparable or even superior to cortisone and calcineurin (without their
side effects!) in regard to diseases of the allergically and
immunologically related spectrum disorder. In patients having
neurodermitis, which has a highly dramatic clinical course, the need,
which is in the foreground for almost all patients, for itching relief
could be dramatically improved in particular in comparison to the
previously ordered cortisone or calcineurin inhibitors. The clinical
relevance results from the secondary results of this cardinal guiding
symptom for neurodermitis: scratching until bloody at the affected skin
areas because of the unrelieved itch, with consequent lichenification. In
contrast to the symptom influence (itching), which only begins within
days after cortisone therapy, the guiding symptom of itching can be
improved within a few minutes using the low-THC plant extract in a
pharmaceutically suitable administration form. Through this improvement
of the clinical symptom "itching", which is in the foreground, secondary
symptoms such as scratch-related skin lesions with bleeding, followed by
subsequent lichenification, are clinically visibly improved within a few
days. This is of very high significance above all for women and/or in the
facial area.

[0017] In addition, this plant extract has not displayed any side effects
up to this point. Therefore, all of the above-mentioned side effects
under the treatment using cortisone or calcineurin inhibitors are not a
concern and/or may even be healed, in particular in regard to the topical
side effects of longer cortisone therapy. The use of cortisone and
calcineurin inhibitors can be completely avoided. For patients who, for
the cited substance classes, are either therapy resistant or were already
suffering from their side effects or who have rejected the therapy using
the substance groups, this represents a completely novel therapy
approach.

[0018] Furthermore, a clinically distinct antimycotic effect, which was
also not suspected up to this point, was shown, which could prove to be
very valuable both topically and also systemically, above all because of
its rapid initial effect, in the further therapy spectrum. This
effectiveness relates to both saprophytes and also dermatophytes and
yeast fungi. The relevance of this antimycotic effect results, beyond the
effectiveness having little or no side effects, from both the necessity
of applying antimycotic agents such as metronidazole (both topically and
also systemically) for various skin diseases, and also its significant
side effect potential.

[0019] According to the surprising effectiveness of the plant extract of
the present invention described above, this extract is also used for the
production of a pharmaceutical, preferably for the treatment of
neurodermitis, contact eczema, allergies, the prevention or treatment of
phototoxic reactions, the treatment of inflammatory, itching dermatoses,
rosacea, perioral dermatitis, acne, acne conglobata, psoriasis (vulgaris,
arthropathica, pustulosa), mosquito bites, skin atrophy (in particular
also cortisone-related skin changes), allergic rhinitis, privinismus,
conjunctivitis, otitis externa, bronchial asthma, Crohn's disease,
ulcerative colitis, sarcoidosis, or inflammatory-rheumatic diseases of
the soft tissue or joints, and mycoses. Inflammatory, itching dermatoses
in the meaning of the present invention are understood in particular as
diseases selected from the group comprising rosacea, perioral dermatitis,
psoriasis vulgaris, psoriasis pustulosa, acne, acne conglobata.

[0020] Inflammatory-rheumatic diseases in the meaning of the present
invention are understood as diseases selected from the group comprising
chronic polyarthritis, Bechterew's disease, psoriasis arthritis,
polymyalgia rheumatica, collagenoses, and vasculitides.

[0021] In the scope of this invention, the term "neuroderm(at)itis" (also,
better: atopical dermatitis or "atopical eczema") is understood as an
increasingly frequently occurring spasmodic skin disease, which occurs in
particular in adolescents. The skin of a neurodermitis sufferer is highly
sensitive in the acute phase and can react allergically to psychic and
physical stressors and to an entire array of individually varying
environmental factors and toxins. In the acute phase, the skin is
inflamed and the affected individual particularly suffers from the
agonizing itching. As far as is known, neurodermitis is not a result of a
disease of the internal organs, but rather of inflammatory free-radical
producing processes of the external skin layers, so that a positive
influence can be taken here by external application in a topical
application form using a dermatological or cosmetic composition, for
example, in the form of salves, creams, or gels.

[0022] "Mycoses" in the meaning of the present invention are fungal
diseases, which are typically triggered by thread fungi or sprout fungi.
A differentiation is made for this purpose between superficial and
systemic mycoses. Superficial mycoses may affect the entire body, foot
fungus (Tinea pedis) is the most well known, but the mucosa may also be
affected (thrush or candidiasis).

[0023] Furthermore, mycoses and neurodermitis may exist adjacent to one
another, in particular in skin folds (behind the knee, etc.).

[0024] The plant extract of the present invention can be obtained by any
extraction method known to one skilled in the art. For extracts which may
also be used as directly applicable liquid pharmaceuticals, the following
extraction agents are suitable: cold water, table salt solution, diluted
acetic acid, sweet wine, ethanol-water mixtures, ethanol, other
low-molecular-weight alcohols, acetone, esters, ethers, and mixtures
thereof. Methanol, organic solvents such as acetone, ether,
dichloromethane, and supercritical gases, vacuum extraction, and
freeze-drying are typical and known to one skilled in the art for
obtaining dry extracts. For this purpose, one may select between simple
extraction methods selected from the group comprising resting maceration,
moving maceration, digestion, percolation, re-percolation, evacolation
and diacolation, and special extraction methods selected from the group
comprising the combination of maceration and percolation, ultrasonic
extraction, counter flow extraction, and extraction using separators,
centrifuges, and decanters. These methods are known to one skilled in the
art and reference is made, for example, to Hagers Handbuch der
Pharmazeutischen Praxis [Hager's Handbook of Pharmaceutical Practice]
(5th edition, volume 2; pages 1026-1030, Springer Verlag,
Berlin-Heidelberg-New York (1991)). Fresh plants or plant parts may be
used as the starting materials, however, one typically starts with dried
plants and/or plant parts, which may be mechanically pulverized before
the extraction. All pulverization methods known to one skilled in the art
are suitable for this purpose, crushing using a mortar is cited as an
example,

[0025] All solvents having a specific polarity, preferably organic
solvents, water (distilled or non-distilled) or mixtures of organic
solvents and water, in particular low-molecular-weight alcohols, esters,
hydrocarbons, ketones, or halogenated hydrocarbons having greater or
lesser water content may be used as the solvent for performing the
extractions. Examples are protic (water, alcohols, acids, primary and
secondary amines) and aprotic (acetonitrile, dimethyl formamide, dimethyl
sulfoxide, hexamethyl phosphoric acid triamine, nitromethane, tear-amine)
solvents, Extraction using water, methanol, ethanol, propanol,
isopropanol, pentane, hexane, heptane, acetone, chloroform, propylene
glycols, polyethylene glycols, ethyl acetate, dichloromethane,
trichloromethane, and mixtures thereof is particularly preferred. The
extraction is typically performed at 15 to 25.degree. C. (aqueous
extracts) or at 20 to 35.degree. C. (low-molecular-weight alcohols),
fundamentally preferably at room temperature, in order to reliably
protect temperature-sensitive extract components. After the extraction,
the obtained raw extracts may optionally be subjected to further typical
steps, such as purification, concentration, and/or de-coloring. If
desired, the extracts thus produced may be subjected to a selective
separation of individual undesired components, for example. The extracts
may subsequently also be subjected to a spray or freeze-drying, for
example. The term "extract" according to the present invention is
accordingly understood as a material and/or material mixture, which is
obtained by one or more extraction and/or other method steps from the
hemp plant.

[0026] In a particularly preferred embodiment, the plant extract of the
present invention is obtained using an extraction medium, solvent, and/or
mixture of solvents selected from the group comprising water, table salt
solution, low-molecular-weight alcohols, acetone, esters, and ethers.
0.9% table salt solution, ethanol, or isopropanol is preferably used as
the extraction medium, more preferably 90% ethanol or 70% isopropanol.

[0027] According to a preferred embodiment of the present invention, the
low-THC Cannabis sativa subspecies sativa variety Futura 75 is used for
obtaining the plant extract. A further aspect of the present invention
relates to a method for producing a plant extract from the flowers and
flower-proximal leaves of a low-THC Cannabis sativa subspecies sativa,
comprising the steps of a) drying the flowers and/or flower-proximal
leaves and/or stalks and/or roots and/or seeds, b) pulverizing the
flowers and/or flower-proximal leaves and/or stalks and/or roots and/or
seeds, and c) extracting the flowers and/or flower-proximal leaves and/or
stalks and/or roots and/or seeds. The method is preferably performed
using flowers and/or flower-proximal leaves, because the most drug is
contained here.

[0028] According to a preferred embodiment, the extraction comprises the
steps C-1) admixing the flowers and flower-proximal leaves for 24
hours-48 hours or 12 hours-48 hours with an extraction medium at room
temperature and C-2) filtering the extract.

[0029] In still a further preferred embodiment, the method of the present
invention comprises the step d) freeze-drying the acquired extract and/or
vacuum extraction of the acquired extract. In a preferred embodiment, the
method of the present invention uses solvents and/or mixtures of solvents
selected from the group comprising water, table salt solution,
low-molecular-weight alcohols, acetone, esters, and ethers, preferably
0.9% table salt solution, ethanol, or isopropanol, more preferably 90%
ethanol or 70% isopropanol as the extraction medium.

[0030] In a particularly preferred embodiment, the low-THC Cannabis sativa
subspecies sativa variety Futura 75 is used in the method of the present
invention. However, it can also be replaced by any other Cannabis sativa
variety having a THC content according to the current state of the
national legal guidelines (in the German narcotics code currently 0.2%).

[0031] A further object of the present invention comprises a
pharmaceutical composition, which comprises a plant extract, preferably
made of the flowers and flower-proximal leaves of a low-THC Cannabis
sativa variety, preferably the low-THC Cannabis sativa subspecies sativa
variety Futura 75.

[0032] The invention also relates to a cosmetic or dermatological
composition in a topical application form, which comprises a plant
extract, preferably made of the flowers and flower-proximal leaves of a
low-THC Cannabis sativa variety, preferably the low-THC Cannabis sativa
subspecies sativa variety Futura 75.

[0033] In a special embodiment, the pharmaceutical or dermatological
composition further comprises pharmaceutically suitable aids and
additives. The pharmaceutical agents and/or compositions of the invention
are produced using typical solid or liquid carriers or diluents and
typical pharmaceutical and technical aids according to the desired type
of application having a suitable dosage in a way known per se. Preferred
preparations comprise an administration form which is suitable for
topical, oral, inhaled, intranasal, enteral or parenteral, for example,
i.p. (intraperitoneal), i.v. (intravenous), i.m. (intramuscular), or
percutaneous application. Such administration forms are, for example,
tablets, film tablets, dragees, pills, capsules, powders, creams, salves,
lotions, liquids, such as syrups, gels, and injectable liquids, for
example, for i.p., i.v., i.m., or percutaneous injection, nasal sprays or
also inhalation sprays, etc. Furthermore; depot forms, such as
implantable preparations, and suppositories are also suitable. The
individual preparations release the extracts according to the invention
to the body gradually or the entire quantity in a short time depending on
their type. For oral administration, capsules, pills, tablets, dragees,
and liquids or other known oral administration forms may be used as the
pharmaceutical preparation. In this case, the pharmaceuticals may be
formulated so that they release the drugs in a short time and discharge
them to the body or have a depot effect, so that a longer-lasting, slow
supply of drug to the body is achieved. The dosing units may contain one
or more pharmaceutically compatible carriers in addition to at least one
plant extract according to the invention, such as materials for setting
the rheology of the pharmaceutical, surfactants, solution mediators,
microcapsules, microparticles, granules, diluents, binders, such as
starch, sugar, sorbitol, and gelatin, and also fillers such as silicic
acid and talcum, lubricants, colorants, odorants, and other materials.

[0034] Corresponding tablets may be obtained, for example, by mixing the
extract according to the invention with known aids, for example, inert
diluents such as dextrose, sugar, sorbitol, mannitol, polyvinyl
pyrrolidone, disintegrating agents such as cornstarch or alginate,
binders such as starch or gelatin, lubricants such as carboxy
polymethylene, carboxy methylcellulose, cellulose acetate phthalate, or
polyvinyl acetate. The tablets may also comprise multiple layers.

[0035] Correspondingly, dragees may be produced by coating cores produced
similarly to tablets using agents typically used in dragee coating, such
as polyvinyl pyrrolidone or shellac, gum Arabic, talcum, titanium oxide,
or sugar. The dragee shell can comprise multiple layers, the aids listed
above for the tablets being able to be used.

[0036] Drugs may also be formulated in the form of a solution, which is
intended for oral or topical administration and which contains, in
addition to an active plant extract according to the invention, a
pharmaceutically compatible oil and/or a pharmaceutically compatible
lipophilic, surfactant substance, and/or a pharmaceutically compatible,
hydrophilic surfactant substance, and/or a pharmaceutically compatible
water-miscible solvent as components. Creams, salves, lotions, and
tinctures may also be used for external application. These administration
forms frequently contain aids, for example, materials for setting the
rheology of the pharmaceutical, surfactants, preservatives, solution
mediators, diluents, materials for increasing the permeation capability
for the extracts according to the invention through the skin, colorants,
odorants, and skin protection agents, such as conditioners and moisture
regulators. Together with the extracts according to the invention, other
drugs may also be contained in the pharmaceutical (Ulimanns Enzyklopadie
der technischen Chemie [Encyclopedia of Technical Chemistry], volume 4
(1953), pages 1-39; J. Pharm. Sei. (1963) 52:918 et seq., H. V.
Czetsch-Lindenwald, Pharm, hd. (1961) 2:72 ff, Fiedler, Lexikon der
Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete [Lexicon of
Aids for Pharmacy, Cosmetics, and Related Fields], Cantor AG (1971)).

[0037] Corresponding cosmetic compositions of the plant extracts according
to the invention may be provided similarly according to the typical
formulations known for one skilled in the art in a topical application
form.

[0038] In a further embodiment, the cosmetic or dermatological preparation
according to the invention can therefore be produced for topical use
("topical composition") in the form of a salve, cream, gel, lotion (skin
cream), paste, or preferably an emulsion. Water-free systems are also
possible. Emulsions are generally understood as heterogenous systems
which comprise two or more liquids which are not miscible or are only
miscible with one another to a limited extent, which are typically
designated as phases. In an emulsion, one of the two liquids is dispersed
in the other liquid in the form of ultrafine droplets. If the two liquids
are water and oil, and oil droplets are finely distributed in the water,
it is an oil-in-water emulsion (O/W emulsion). The fundamental character
of a O/W emulsion is given by the water. In a water-in-oil emulsion (W/O
emulsion), the reverse principle applies, in that the fundamental
character is determined here by the oil. Furthermore, mixed systems such
as water-in-oil-in-water emulsions (W/O/W emulsion) and
oil-in-water-in-oil emulsions (O/W/O emulsions) are known. All cited
emulsions are suitable according to the invention.

[0039] The water-free systems suitable according to the invention include
pure oil preparations such as skin oils. Pastes which are also usable
containing the preparation according to the invention are distinguished
in that they comprise the same or similar components as an emulsion but
are essentially water-free. The terms oil phase and lipid phase are used
synonymously in the scope of the present invention. In a further
preferred embodiment, the preparation according to the invention can
contain an emulsifier as a further component. In a very preferred
embodiment, this emulsifier can be an O/W emulsifier.

[0040] Emulsifiers may advantageously be selected from the group of
non-ionic, anionic, cationic, or amphoteric emulsifiers.

[0041] The plant extracts according to the invention may also be applied
in suitable solutions, such as a physiological table salt solution, as an
infusion or injection solution, nasal sprays, or eye drops. For a
parenteral application, the drugs may be dissolved are suspended in a
physiologically compatible diluent. Oily solutions, such as solutions in
sesame oil, castor oil, and cotton seed oil, are also suitable as
diluents. To increase the solubility, solution mediators, such as benzyl
benzoate or benzyl alcohol, may be added.

[0042] In a special embodiment, the pharmaceutical or dermatological
composition of the present invention contains further drugs and/or aids,
preferably dexpanthenol. Dexpanthenol encourages the adhesion as an aid
in aqueous compositions, such as aqueous sprays. Dexpanthenol is
preferably used in nasal sprays, oral sprays, and eye drops/eye
ointments. In a further embodiment, the pharmaceutical composition of the
present invention additionally contains a pharmaceutically effective
quantity of the protein filaggrin, either jointly with or spatially
separated from the plant extract according to the invention.

[0043] Filaggrin is a histidine-rich cationic protein, and/or a group of
isoform proteins, which originate in the keratinization process of the
skin from profilaggrin. Filaggrin is a protein of the keratinizing
epithelial cells of the epidermis, which aggregates the filaments and
originates through post-translational modification of the profilaggrin in
the keratinocytes. Filaggrin has structure-forming functions for the
epidermis. A genetically-based lack of filaggrin has recently been
formulated as one cause for the occurrence of a neurodermitis.

[0044] A further aspect of the present invention relates to the use of the
plant extract or the pharmaceutical composition for the production of a
pharmaceutical for the treatment of neurodermitis, allergies,
inflammatory, itching dermatoses, mosquito bites, skin atrophy, allergic
rhinitis, privinismus, otitis externa, bronchial asthma, Crohn's disease,
ulcerative colitis, sarcoidosis, conjunctivitis, inflammatory-rheumatic
diseases, and mycoses, or the prevention or treatment of phototoxic
reactions. The plant extract or the pharmaceutical composition is
preferably used in topical applications together with a pharmaceutically
effective quantity of the protein filaggrin.

[0045] In another aspect, the present invention relates to the use of the
plant extract according to the invention as a medication for the
effective treatment of patients who respond inadequately or poorly to a
therapy using a typical cortisone dose and/or reject cortisone treatment
and/or may not be treated using cortisone-containing preparations because
of side effects. In these cases, typically only the strongest therapeutic
agents known up to this point (besides the cortisones)--calcineurin
inhibitors--may be used instead, which very frequently only result in
inadequate symptomatic relief of the symptoms, which are subjectively
extraordinarily agonizing to the patients. Because the treatment can
additionally be subject to severe side effects, the situation has still
further problems. Therefore, we have searched for a possibility of
supplementing and/or replacing calcineurin inhibitors by more effective
and better compatible medications for the treatment of neurodermitis and
also, vice versa, calcineurins. The present invention thus provides an
effective therapy, which is free of side effects, of these patients (in
the scope of the present invention designated as "therapy failures").
These therapy failures may, as specified above, be treated effectively
using the cannabis extract according to the invention instead of
cortisone, so that the calcineurin inhibitors do not have to be used
instead, and vice versa.

[0046] The invention therefore also relates to a replacement therapy for
cortisone and/or calcineurin-inhibitor therapy, the plant extract
according to the invention being administered to the patient in a
pharmaceutical or topical composition.

[0047] A further aspect of the present invention relates to the use of
cannabinoids and/or the plant extracts according to the invention for the
production of a pharmaceutical for the treatment of neurodermitis
(atopical dermatitis), allergies, inflammatory, itching dermatoses,
mosquito bites, skin atrophy, allergic rhinitis, privinismus, otitis
externa, bronchial asthma, Crohn's disease, ulcerative colitis,
sarcoidosis, conjunctivitis, mycoses, or inflammatory-rheumatic diseases,
or the prevention or treatment of phototoxic reactions. These indications
may also be treated jointly.

[0048] The cannabinoids are preferably used together with filaggrin in
topical applications.

[0049] However, the treatment of neurodermitis and mycoses, optionally
present jointly, using the plant extracts or cannabinoids according to
the invention is particularly preferred.

[0050] In a further embodiment, the invention relates to the treatment of
acute outbreaks of neurodermitis, which are possibly accompanied by
strong itching. In these cases, a dosage of 0.1-5 g/l, in particular
0.5-1 g/l plant extract in a solvent, preferably isopropanol, has proven
to be suitable for treating the acute outbreaks. Furthermore, a solid
composition can be selected, which contains 2-70%, in particular 5 to 10%
of the plant extract according to the invention.

[0051] The plant extracts according to the invention are therefore
particularly suitable for the treatment of neurodermitis, because itching
relief advantageously occurs. In a further preferred embodiment, the
plant extract is to be applied in a lower dose (e.g., 1/3 or 1/2) for
posttreatment.

[0052] The invention will be explained hereafter on the basis of examples,
without being restricted to these examples, however.

1. PRODUCTION OF THE EXTRACT

1.1 Starting Material:

[0053] The starting material is formed by flowers and/or flower-proximal
leaves, preferably dried after harvest, of the low-THC industrial hemp
variety (e.g., variety Futura 75). These are dried in dry air ("attic")
and at low temperatures (<35.degree. C.) hanging down on lines.

1.2 Preparation:

[0054] During the preparation, the dried flowers and flower-proximal
leaves are initially finely ground. The finely ground granules are
subsequently introduced in a ratio of 1:4 to 1:5 (volume ratios) into
various solvents and remain therein for 24 hours to 48 hours in
light-proof brown bottles for the extraction procedure at room
temperature, but not higher.

[0055] The extract is subsequently filtered off and stored in light-proof
bottles at approximately 2.degree. C. Depending on the intended use,
aqueous extracts using water or alcoholic extracts made of ethanol and
isopropanol are suitable for the production of the extract. These are to
be stored refrigerated until the development of suitable
stabilizers--like the clinically highly effective creams which are
producible therefrom (see below). An aqueous extract diluted in the ratio
1:5 is outstandingly suitable for nose, eye, and ear drops. Hair
tinctures for the treatment of diseases of the scalp may be produced from
the isopropyl extract. The ethanolic extract is thus suitable for the
production of preparations (e.g., creams) for the remaining skin areas,
beginning the treatment in the event of particularly pronounced symptoms,
in particular itching, using an ethanolic or isopropanolic tincture also
having proven itself here. Tinctures (undiluted) are also the agent of
choice for the treatment of mycoses, i.e., for the first treatment stage,
until the superficially visible efflorescences have died down, because
they result in a particularly rapid initial effect.

2. Clinical Effectiveness

2.1 General

[0056] Additional topical or systemic pharmaceuticals, such as
antihistamines, cortisone preparations, or calcineurin inhibitors, were
not used as a supplement in a single one of the clinical applications
described hereafter in the scope of medical treatment attempts.

[0057] All treated patients were made aware of the medical treatment
attempt character of their individually titrated topical plant extract
therapy and notified of the conventionally available therapeutic
alternatives, with which they had typically previously been treated
already with unsatisfactory results. All patients preferred the treatment
using the plant extract of the present invention and/or a cream into
which this plant extract was incorporated.

[0058] Undesired pharmaceutical effects, in particular allergic reactions,
did not occur in any of the patients, who were partially treated up to 11
months and also intermittently upon lack of symptoms.

[0059] All patients requested information about how they could acquire
low-THC cannabis preparations after the medical treatment attempt.

2.2 Treatment of Neurodermitis:

[0060] In the scope of medical treatment attempts, 21 patients of various
ages having chronic severe neurodermitis were treated an average of 7 to
10 days. All patients had in common: Chronic severe course with
unbearable itching, previous treatment using cortisones and calcineurin
inhibitors with inadequate effect and/or termination of treatment
provoked by side effects or refusal of the patients with respect to
(further) cortisone therapy or treatment using calcineurin inhibitors.

[0061] In all patients, there was significant relief and/or abatement of
the leading symptom of itching. The initial effect began within minutes
after the first topical application. The duration of effect was
approximately 12-24 hours, The most substantial efflorescences
disappeared in 3-7 days. If the patients forgot to continue the local
treatment because of the symptomatic relief and/or freeing, the disease
symptoms recurred after days to weeks, but abated just as rapidly and
significantly as under the initial therapy under renewed treatment. There
was not a single therapy failure among the 21 patients treated using the
extract.

2.3 Treatment of Mycoses

[0062] In the case of a very overweight 18-year-old patient, itching
mycosis occurred in the area of the left sub-mammary fold, i.e., an
intertriginous area. The application of a pharmaceutical composition
according to the invention twice per day already resulted in significant
symptom improvement, which could also be visually confirmed on the basis
of the efflorescences, after 2 days. The symptoms were completely abated
after a week of further treatment. A duration of at least 14 days is
typically used for topical antimycotic therapy. A reoccurrence has not
occurred in the following 5 summer months which have been able to be
observed since then.

[0063] The conventional therapy duration of 14 days was applied in a
58-year-old male patient having a freshly occurring Tinea pedis having
strong keratinization in the heel area, in order to also achieve
effective antimycotic concentrations in lower lying skin areas. In
addition to mechanical abrasion of the keratinized skin areas, the
undiluted (applied in the ratio 1:4) fresh plant extract of the present
invention was applied twice per day in the first three days of treatment
for this patient. After the drying, this treatment was supplemented by
the application of a cream, which contain this extract. From the 3rd to
the 14th day of treatment, the cream was only still applied once or twice
per day and wiped off after an action time of approximately one hour, in
order to avoid laundry contamination because of the chlorophyll, which
was not yet eliminated in the experimental batches. After this treatment,
the mycosis was completely eliminated.

[0064] A 57-year-old female patient, who had suffered from
genetically-related neurodermitis since her youth, reported for years of
repeatedly recurring skin mycosis in the area of the
neurodermitis-related damage of the integument, in particular in the
intertriginous pedal interdigital area, which had previously been
repeatedly affected. Since the patient has been treated using the topical
preparations of the plant extract of the present invention, which has
been 11 months in the meantime, not a single reoccurrence of a mycosis
has occurred.

2.4 Treatment of Urticaria

[0065] In three patients, urticaria occurred on both forearms with
pronounced rashes and extremely strong itching after garden work (pulling
weeds in perennial beds). These symptoms were able to be abated
completely and lastingly using immediately applied cream made of wool wax
alcohol ointment (DAB 998), into which the alcoholic plant extract of the
present invention was introduced until saturation, within 10-30 minutes
(itching) and 30-60 minutes (rash) after a single application.

2.5 Treatment of Mosquito Bites

[0066] Mosquito bites having severe urticarial hives, approximately the
size of a 5-mark piece, were able to be abated completely and lastingly
in 4 cases in patients of various ages using a single application of a
cream which contains the plant extract of the present invention.

[0067] In a further male 55-year-old patient, an extremely pronounced
urticaria occurred in the area of the entire left middle and lower belly
after an insect bite approximately 3 cm left of the paraumbilical. The
finding was so severe that in this case, without clinical previous
experience using the plant extract of the present invention, treatment
would very probably have been local and systemic using dexamethasone (a
particularly high-strength cortisone). After no sign of beginning
anaphylactic shock was recognizable in the patient, however, firstly a
treatment attempt using the plant extract of the present invention and/or
a cream which contain this plant extract was performed under medical
supervision. The itching was extensively abated already after
approximately 20-30 minutes, the welt at the bite location had
significantly receded, the swelling had regressed, and the rash was also
relieved. Itching episodes did return over the next 5 days in this
patient and the rash also had not yet completely disappeared, but these
remaining symptoms reacted regularly to the renewed application of the
cream.

3. Possible Action Mechanism

[0068] The rapid initial effect and the long action duration of the plant
extract of the present invention indicate two different engagement
points:

[0069] 1. The rapid initial effect, which occurs within minutes, leads to
the suspicion that the plant extract reacts, inter alia, with the itching
receptors of the sensory nervous system of the skin. The fact that at
this time the mediators of the mast cells (e.g., histamines and
leukotrienes) have already been distributed and cause the agonizing
symptoms in the skin tissue indicate this. An engagement point on the
corresponding receptors may already be assumed because the symptomatic
easing by scratching over the skin defect also destroys these receptors.
Therefore, no action potentials which generate itching may still be
fired. Therefore, the short-term active local effect of the plant extract
is also to be explained via these receptors, although not by their
destruction, but, for example, via a possible competitive effect.

[0070] 2. The long effectiveness duration can be explained via an entirely
different action mechanism, however. This is probably a secretion
inhibition of the histamines and leukotrienes from the mast cells which
is caused by a plant extract. The fact that two types of endocannabinoid
receptors have already been detected on the mast cells of humans suggests
this. It has thus also been shown that the control center of all
cellularly-mediated immunological reactions, the mast cells, can also be
decisively influenced by cannabinoids. It follows from this finding that
the other diseases discussed in this invention, which are also mediated
via mast cell reactions, are favorably influenced.

[0071] 3. Furthermore, it follows from these considerations that all
immune reactions mediated via mast cells are favorably influenced by
cannabinoids.